Cholinergic neuronal defect without cell loss in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease

Orexin loss in Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin, a protein of unknown function. Mutant huntingtin forms intracellular aggregates and is associated with neuronal death in select brain regions. The most studied mouse model (R6/2) of HD replicates many features of the disease, but has been reported to exhibit only very little neuronal death. We describe for the first time a dramatic atrophy and loss of orexin neurons in the lateral hypothalamus of R6/2 mice. Importantly, we also found a significant atrophy and loss of orexin neurons in Huntington patients. Like animal models and patients with impaired orexin function, the R6/2 mice were narcoleptic. Both the number of orexin neurons in the lateral hypothalamus and the levels of orexin in the cerebrospinal fluid were reduced by 72% in end-stage R6/2 mice compared with wild-type littermates, suggesting that orexin could be used as a biomarker reflecting neurodegeneration. Our results show that the loss of orexin is a novel and potentially very important pathology in HD

Inclusion body myositis Clinical features and clinical course of the disease in 64 patients

The clinical features of inclusion body myositis (IBM) were of minor importance in the design of consensus diagnostic criteria, mainly because of controversial views on the specificity of signs and symptoms, although some authors reported "typical" signs. To re-assess the clinical spectrum of IBM, a single investigator using a standard protocol studied a cohort of 64 patients cross-sectionally. Symptom onset was before the age of 50 years in 20% of cases. Only a few patients (14 %) started with weakness other than that of quadriceps, finger flexor or pharyngeal muscles. The sequence of power loss was erratic, but onset of symptoms with quadriceps weakness predicted an earlier onset of dysphagia in older patients (> or = 56 years) compared with younger ones ( <56 years) (p = 0.02). Despite widespread weakness patients had favourable scores on three commonly used function scales and they kept their employment. Complete wheel-chair dependency was rare (3 %). A dominant characteristic was the anatomical distribution of afflicted muscles: ventral extremity muscle groups were more affected than dorsal muscle groups and girdle muscles were least affected, the latter preserving postural stability. Ankylosis, especially in extension of the fingers,was frequently present. Together with the sparing of intrinsic hand muscles it was helpful in the preservation of many skillful movements. IBM has a unique distribution of muscle weakness. Ankylotic contractures are common. We feel that their joint impact on daily functioning is characteristic for the diseas

Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo

We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval = -2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activit

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud's phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud's phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud's phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease 'retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations'. We propose diagnostic criteria to facilitate clinical recognition and future studies